Suppression of Gonadotropins and Estradiol in Premenopausal Women by Oral Administration of the Nonpeptide Gonadotropin-Releasing Hormone Antagonist Elagolix

Abstract

Oral administration of a nonpeptide GnRH antagonist, elagolix, suppressed the reproductive endocrine axis in healthy premenopausal women. These results suggest that elagolix may enable dose-related pituitary and gonadal suppression in premenopausal women as part of treatment strategies for reproductive hormone-dependent disease states.

Elagolix for the management of heavy menstrual bleeding associated with uterine fibroids: results from a phase 2a proof-of-concept study

“…Consistent with the phase 1 hormone data in healthy premenopausal women (17), administration of elagolix resulted in dosedependent reductions in serum E 2 concentrations, with 200 mg BID and 300 mg BID resulting in median E 2 concentrations of 11 pg/mL through month 2 (Supplemental Table 9). With add-back therapies, numerically higher E 2 concentrations were observed, with median E 2 concentrations of 22 to 23 and 42 pg/mL, respectively, for the elagolix 200 mg BID plus low-dose E 2 / NETA and elagolix 300 mg BID plus E 2 /cyclical EP groups.…”

“…Elagolix is an oral, nonpeptide GnRH antagonist that suppresses the pituitary-ovarian axis in a dose-dependent manner, with partial suppression at lower doses and nearly full suppression at higher doses in previous phase 1 (17) and phase 2 research (18). Phase 2 studies in women with endometriosis-associated pain demonstrated the efficacy of elagolix in reducing pain symptoms, with an acceptable safety and tolerability profile (19)(20)(21)(22).…”

Endometriosis

“…Although the pathogenesis of endometriosis and associated pain and infertility remains incompletely understood, therapies aimed at correcting progesterone resistance (e.g., selective progesterone-receptor modulators) and systemic immune dysfunction, as well as those targeting angiogenesis, inflammation, neurotropism, and pain transmission, including a neuropathic component, warrant further study. Oral GnRH antagonists and other small molecules that suppress circulating estradiol levels to the range suggested by the estrogen threshold hypothesis (30 to 45 pg per milliliter) 49 also warrant investigation. Studies of complementary or alternative therapies are needed.…”

Medical Treatment of Uterine Leiomyoma

“…These properties suggest that elagolix may enable doserelated pituitary and gonadal suppression in premenopausal women as part of treatment strategies for reproductive hormone-dependent disease states. 93…”